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The aims of this work were: (1) to evaluate whether a short\u2010term regulation of intestinal MRP2 barrier function takes place in vivo after luminal incorporation of nutrients and (2) to explore the underlying mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>MRP2 activity and localization were assessed in an in vivo rat model with preserved irrigation and innervation. Nutrients were administered into distal jejunum. After 30\u2010minutes treatments, MRP2 activity was assessed in proximal jejunum by quantifying the transport of the model substrate 2,4\u2010dinitrophenyl\u2010S\u2010glutathione. MRP2 localization was determined by quantitative confocal microscopy. Participation of extracellular mediators was evaluated using selective inhibitors and by immunoneutralization. Intracellular pathways were explored in differentiated Caco\u20102 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Oleic acid, administered intraluminally at dietary levels, acutely stimulated MRP2 insertion into brush border membrane. This was associated with increased efflux activity and, consequently, enhanced barrier function. Immunoneutralization of the gut hormone glucagon\u2010like peptide\u20102 (GLP\u20102) prevented oleic acid effect on MRP2, demonstrating the participation of this trophic factor as a main mediator. Further experiments using selective inhibitors demonstrated that extracellular adenosine synthesis and its subsequent binding to enterocytic A2B adenosine receptor (A2BAR) take place downstream GLP\u20102. Finally, studies in intestinal Caco\u20102 cells revealed the participation of A2BAR\/cAMP\/PKA intracellular pathway, ultimately leading to increased MRP2 localization in apical domains.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings reveal an on\u2010demand, acute regulation of MRP2\u2010associated barrier function, constituting a novel physiological mechanism of protection against the absorption of dietary xenobiotics in response to food intake.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13514","type":"journal-article","created":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T07:48:26Z","timestamp":1590997706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon\u2010like peptide\u20102\u2010mediated mechanism"],"prefix":"10.1111","volume":"230","author":[{"given":"Guillermo N.","family":"Tocchetti","sequence":"first","affiliation":[{"name":"Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET) National University of Rosario (UNR) Rosario Argentina"},{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University of Heidelberg Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila J.","family":"Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET) National University of Rosario (UNR) Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Zecchinati","sequence":"additional","affiliation":[{"name":"Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET) National University of Rosario (UNR) Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maite R.","family":"Arana","sequence":"additional","affiliation":[{"name":"Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET) National University of Rosario (UNR) Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan P.","family":"Rigalli","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology University of Heidelberg Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda L.","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Institute of Experimental Physiology (IFISE) National Scientific and Technical Research Council (CONICET) National University of Rosario (UNR) Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvina S. 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